Due to the increasing size of the elderly population and negative changes in dietary habits, degenerative brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease and the like are rapidly increasing. Among them, Alzheimer's disease, also known as senile dementia, is a representative degenerative brain disease, causing memory loss, cognitive impairment and death caused by complications if prolonged. Alzheimer's disease may occur at relatively early ages of 40s to 50s. Prevalence increases with age, reaching 40-50% in those who are 85 to 90 years old.
A lot of research results on various degenerative brain diseases including Alzheimer's disease are being reported and drugs targeting various underlying mechanisms are being developed. However, currently available drugs merely slow the progress of diseases and cannot cure them. Thus, at present, early diagnosis is ideal to achieve the best prognosis. Since the pathological change of the degenerative diseases begin about 7 years before symptoms occur, early diagnosis and treatment is essential.
There are two hypotheses as to the causes of Alzheimer's disease. Amyloid plaques and neurofibrillary tangles (NFT) have been found in the brain tissue of patients with Alzheimer's disease. The amyloid plaques are formed outside the nerve cells as amyloid peptides are deposited, and the neurofibrillary tangles are formed inside the nerve cells due to accumulation of tau proteins. The presence of β-amyloid leads to a significant change in biochemical processes, thereby inducing deposition of other proteins and activating phagocytosis by microglia, ultimately resulting in loss of nerve cells and cognitive impairment. The initiation of aggregation of β-amyloid plaques occurs long before clinical symptoms are observed. The current “minimal microscopic criteria for the diagnosis of Alzheimer's disease” are based on the quantity of the β-amyloid plaques detected in the brain. The plaque mainly consists of β-amyloid peptides consisting of 39 to 43 amino acids arranged in 13 sheet structure. Among these, β-amyloid 42 is more toxic and forms plaques more easily than β-amyloid 40 due to the presence of additional hydrophobic amino acid residues.
Accordingly, a compound selectively and strongly binding to β-amyloid aggregates may be developed into a therapeutic agent that suppresses the β-amyloid plaque formation and stops progression of Alzheimer's disease or a molecular probe for β-amyloid aggregates that can be used to diagnose Alzheimer's disease. Until recently, it was impossible to know whether β-amyloid plaques are present in the brain of a patient who is suffering or suspected to be suffering from Alzheimer's disease while the patient is alive. Alzheimer's disease can only be definitively determined based upon staining of brain tissue. The presence of amyloid in the brain can be easily detected by staining the brain tissue with thioflavin S represented by Chemical Formula 1 or congo red represented by Chemical Formula II. When stained with congo red, the amyloid exhibits yellowish green color, which is due to the β sheet structure of the amyloid protein.

Radioligands that have been reported so far are known to bind at three different sites of the β-amyloid plaque: congo red (Chemical Formula II)-binding site, thioflavin T (Chemical Formula III)-binding site and FDDNP (Chemical Formula IV)-binding site. Among them, the site where thioflavin T binds to the β-amyloid plaque is being studied the most actively.

Thioflavin S, having among the highest sensitivities in detection of senile plaques, is usually used to detect amyloid plaques from the brain tissue of a patient with Alzheimer's disease after death.
In contrast, thioflavin T represented by Chemical Formula III is frequently used as a reagent for studying how the soluble amyloid protein turns into fibrillar aggregates of β sheet structure. Although thioflavin T strongly binds to the β-amyloid plaque, it cannot pass through the blood-brain barrier well when injected into the bloodstream because it exists in the form of an ionic salt.
Recently, electrically neutral derivatives having the 2-arylbenzothiazole structure of thioflavin T but no charge have been developed. These derivatives strongly bind to the β-amyloid plaque and pass through the blood-brain barrier easily. Thereafter, various other analogues having diaryl or conjugated diaryl structures which are characteristic of the 2-arylbenzothiazole were developed by numerous researchers. They were labeled with radioisotopes such as F-18, C-11, I-123, I-125, etc. to detect β-amyloid plaque in vivo and study distribution thereof.

[11C]PIB (Chemical Formula V, Pittsburgh compound B) is a neutral derivative of the ionic salt thioflavin T. It strongly binds to the β-amyloid plaque and is labeled with C-11 for use as a radiopharmaceutical for positron emission tomography (PET). However, because the half-life of C-11 is only 20 minutes, it is limited in preparation and development of diagnostic reagents. Thus, research is underway into a molecular probe labeled with F-18 (half-life=110 minutes). However, compounds labeled with F-18 tend to have difficulty in passing through the blood-brain barrier because of increased lipophilicity, and it is difficult to obtain clear brain images.
Recently, a stilbene derivative (Chemical Formula VIII, [18F]BAY94-9172 or [18F]florbetaben) having short-lengthed F-18-containing ethylene glycol has been reported. This stilbene derivative is known to easily pass through the blood-brain barrier because of decreased lipophilicity due to the ethylene glycol group.

Some of the currently available brain disease-related drugs have inadequate lipophilicity (logP) thus being incapable of passing through the blood-brain barrier. A logP of 2 to 3 enables effective passage through the blood brain barrier. However, F-18-labeled compounds obtained by nucleophilic substitution have increased lipophilicity because of the additionally introduced alkyl groups, and thereby have difficulty in passing through the blood-brain barrier.
The inventors have sought for an F-18-labeled compound capable of solving this problem. They have realized that by introducing a hydroxyl group at an alkyl residue labeled with F-18, a compound may be provided with an adequate logP and be made to pass through the blood-brain barrier easily.